safety and pharmacology of snx-5422 plus everolimus in subjects with neuroendocrine tumors

Conditions: Cancer

Summary: study is designed to determine the maximum tolerated dose (mtd) of snx-5422 when given in combination with everolimus.

heat shock protein 90 (hsp90) plays a central role in the maturation and maintenance of numerous proteins, for example her2 and mutated egfr, that are critical for tumor cell viability and growth; snx-5422 is a pro-drug of snx-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (hsp90). hsp90 has been found to be expressed in 95% of subjects with pancreatic neuroendocrine tumors. this study will determine the mtd of snx-5422 when given in combination with everolimus in patients with neuroendocrine tumors.the clinical starting dose of 50 mg/m2 qod for snx-5422 in combination with daily everolimus is 50% of the snx-5422 qod mono-therapy mtd. the choice to continue once every other day snx-5422 dosing is based on the safety and efficacy profiles from prior studies, so that drug holidays are interspersed into weekly dosing. the planned subsequent dose levels are 75% and 100% of the snx-5422 qod mono-therapy mtd.

Eligibility criteria:
inclusion criteria: * males or non-pregnant, non-breastfeeding females 18 years-of-age or older. * archived neuroendocrine tumor sample or biopsy sample (will also be used for genetic testing). * pathologic evidence of chemo-resistant small cell lung cancer (relapse \ 90 days after first line), locally advanced metastatic neuroendocrine tumor of gastro-entero, pancreatic, pulmonary (other than small cell lung) or thymic origin, or advanced renal cell carcinoma for which everolimus is indicated. * measurable (recist) indicator lesion not previously irradiated. * life expectancy of at least 3 months. * no more than 4 prior lines of systemic anti-cancer therapy. * karnofsky performance score ≥70. * adequate baseline laboratory assessments, including * absolute neutrophil count (anc) ≥1.5 x 109/l. * wbc \>3000/microliter * platelet count of ≥100 x 109/l. * total bilirubin level ≤1.5 times institutional upper limit of normal (uln), alanine aminotransferase or aspartate aminotransferase ≤2 x uln * hemoglobin ≥9 mg/dl. * creatinine \<1.5 x upper limit of normal or estimated plasma creatinine clearance of ≥40 ml/min * signed informed consent form * recovered from toxicities of previous anticancer therapy * subjects with reproductive capability must agree to practice adequate contraception methods. exclusion criteria: * subjects in whom everolimus is contraindicated. * subjects with clinically significant interstitial lung disease, or obstructive disease without sufficient reserve * carcinoid with hormone related symptoms * neuroendocrine cancer of the thyroid or thymus. * rare pancreatic neuroendocrine cancers such as, insulinomas, glucagonomas, gastrinomas. * prior treatment with any hsp90 inhibitor. * prior failed treatment with mtor inhibitors * cns metastases that are symptomatic and /or requiring escalating doses of steroids. * major surgery or significant traumatic injury within 4 weeks of starting study treatment. * conventional chemotherapy or radiation within 4 weeks. * palliative radiation within 2 weeks. * the need for treatment with medications with clinically-relevant metabolism by the cytochrome p450 (cyp) 3a4 isoenzyme within 3 hours before or after administration of snx-5422 * screening ecg qtc interval ≥470 msec for females, ≥450 msec for males. * at increased risk for developing prolonged qt interval, including hypokalemia or hypomagnesemia, unless corrected to within normal limits prior to first dose of snx-5422; congenital long qt syndrome or a history of torsade de pointes; currently receiving anti-arrhythmics or other medications that may be associated with qt prolongation. * patients with chronic diarrhea or with grade 2 or greater diarrhea despite appropriate medical management. * gastrointestinal diseases or conditions that could affect drug absorption, including gastric bypass. * gastrointestinal diseases that could alter the assessment of safety, including irritable bowel syndrome, ulcerative colitis, crohn's disease, or hemorrhagic coloproctitis. * history of documented adrenal dysfunction not due to malignancy. * known seropositive for human immunodeficiency virus (hiv) or hepatitis c virus (hcv). * history of chronic liver disease. * active hepatitis a or b. * current alcohol dependence or drug abuse. * use of an investigational treatment from 30 days prior to the first dose of snx-5422 and during the study. * glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected by ophthalmological examination. * other serious concurrent illness or medical condition. * psychological, social, familial, or geographical reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process.

Keywords: neuroendocrine tumor hsp90